The invention pertains to novel N-acyl 2-arylcyclopropylmethylamine derivatives having drug and bio-affecting properties, to their preparation, to pharmaceutical formulations containing them and to methods of using them. These compounds possess melatonergic properties that should make them useful in treating certain medical disorders.
Melatonin (i; N-acetyl-5-methoxytryptamine) is a hormone which is synthesized and secreted primarily by the pineal gland. In mammals, melatonin levels show a cyclical, circadian pattern, with highest levels occurring during the dark period of a circadian lightdark cycle. Melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in photoperiodic mammals, the control of circadian rhythms and the modulation of retinal physiology. ##STR1##
Recent evidence demonstrates that melatonin exerts its biological effects through specific receptors. Use of the biologically active, radiolabelled agonist .sup.125 I!-2-iodomelatonin has led to the identification of high affinity melatonin receptors in the central nervous systems (CNS) of a variety of species. The sequence of one such high affinity melatonin receptor, cloned from frog melanocytes, has been reported. In mammalian brain, autoradiographic studies have localized the distribution of melatonin receptors to a few specific structures.
Although there are significant differences in melatonin receptor distribution even between closely related species, in general the highest binding site density occurs in discrete nuclei of the hypothalamus. In humans, specific .sup.125 I!-2-iodomelatonin binding within the hypothalamus is completely localized to the suprachiasmatic nucleus, strongly suggesting that melatonin receptors are located within the human biological clock.
Exogenous melatonin administration has been found to synchronize circadian rhythms in rats (Cassone, et al., J. Biol. Rhythms, 1:219-229, 1986). In humans, administration of melatonin has been used to treat jet-lag related sleep disturbances, considered to be caused by desynchronization of circadian rhythms (Arendt, et al., Br. Med. J. 292:1170, 1986). Further, the use of a single dose of melatonin to induce sleep in humans has been claimed by Wurtman in International Patent Application WO 94/07487.
Melatonin binding sites have been found in diverse tissues of the body--i.e., in the retina, superchiasmatic nucleus, spleen, etc. This means that melatonin exerts multiple physiological effects and is not highly selective. The potential for side effects with melatonin use is large. Melatonin agonists should be more selective than melatonin and have fewer side effects. Suitable melatonin agonists could overcome melatonin's drawbacks, resulting in products having more predictable and, possibly, sustained activity.
Melatonin agonists should be particularly useful for the treatment of chronobiological disorders. They would also be useful for the further study of melatonin receptor interactions as well as in the treatment of conditions affected by melatonin activity, such as depression, work-shift syndrome, sleep disorders, glaucoma, reproduction, cancer, immune disorders, neuroendorine disorders, and a variety of sleep disorders.
Aside from simple indole derivatives of melatonin itself, various amide structures have been prepared and their use as melatonin ligands disclosed. In general these amide structures can be represented as: ##STR2## wherein Z is an aryl or heteroaryl system attached by a two carbon chain to the amide group. Some specific examples follow.
Yous, et al. in European Patent Application EPA 527 687A disclose, as melatonin ligands, ethylamines having cyclic substituents, 1, ##STR3## wherein Ar' is, inter alias, a substituted or unsubstituted benzob!thiophen-3-yl, benzimidazol-1-yl, benzob!furan-3-yl, 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, or indazol-3-yl radical; R.sub.1 is, inter alia, an alkyl or cycloalkyl group; and R.sub.2 is hydrogen or lower alkyl.
Langlois, et al., in Australian Patent Application AU-A48729/93 disclose arylalkyl(thio)amides 2 as melatonergic ligands, ##STR4## wherein R.sub.1 is hydrogen or lower alkyl; R.sub.2 is hydrogen, halogen, or lower alkyl; R.sub.3 and R.sub.4 are identical or different groups including, inter alia, hydrogen, halogen, or lower alkyl; R.sub.5 is hydrogen or lower alkyl; X is sulfur or oxygen and R.sub.7 is, inter alia, lower alkyl or alkenyl.
However, these references do not teach or suggest the novel melatonergic aryl cyclopropylmethylamine derivatives of the present invention.
A number of compounds containing structural elements common to the compounds of the present invention have been disclosed, although melatonergic properties have not been claimed for any the compounds within these disclosures.
Matsuda, et al., in international patent application W095/22521 disclose 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides 3 as N-methyl-D-aspartate (NMDA) receptor antagonists, wherein R.sub.1 represents, inter alia, a C.sub.1 -C.sub.5 linear saturated aliphatic, a C.sub.1 -C.sub.5 linear unsaturated aliphatic, a branched aliphatic, or a phenyl group which may be substituted with one to three substituents selected independently from the group consisting of halogen, C.sub.1 -C.sub.4 alkyl, nitro, amino, hydroxy, and C.sub.1 -C.sub.4 alkoxy. ##STR5##
The 1,2-diarylcyclopropane derivatives of type 4 are disclosed in NE 6701256 as having CNS stimulant properties, ##STR6## Ar.sub.1 and Ar.sub.2 are independently and optionally substituted phenyl; R.sub.1 is inter alia hydrogen, lower alkyl or acyl; R.sub.2 is inter alia alkyl, cycloalkyl or aralkyl.